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Amezalpat
Amezalpat
CAS 1616372-41-8
MF C34H41N3O4 MW555.7 g/mol
- [1,1′-Biphenyl]-3-acetic acid, 3′-[3-[1-[[4-(1,1-dimethylethyl)phenyl]methyl]-4-ethyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl]propyl]-4-ethoxy-
- 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic acid
- 3′-(3-(1-((4-(1,1-DIMETHYLETHYL)PHENYL)METHYL)-4-ETHYL-4,5-DIHYDRO-5-OXO-1H-1,2,4-TRIAZOL-3-YL)PROPYL)-4-ETHOXY(1,1′-BIPHENYL)-3-ACETIC ACID
2-[5-[3-[3-[1-[(4-tert-butylphenyl)methyl]-4-ethyl-5-oxo-1,2,4-triazol-3-yl]propyl]phenyl]-2-ethoxyphenyl]acetic acid
peroxisome proliferator-activated receptor alpha (PPARα) antagonist, antineoplastic, TPST 1120, FDA Fast Track, Orphan Drug, 1EQ4LQN9N3
Amezalpat (formerly TPST-1120) is an investigational, oral, small-molecule inhibitor targeting peroxisome proliferator-activated receptor alpha (PPAR being developed by Tempest Therapeutics. It works by directly targeting tumor cells and reducing immune suppression in the tumor microenvironment. In combination with atezolizumab and bevacizumab, it has shown improved survival in hepatocellular carcinoma (HCC) patients, receiving FDA Fast Track and Orphan Drug designations.
Key Details on Amezalpat
- Indication: Primarily being studied for unresectable or metastatic hepatocellular carcinoma (liver cancer).
- Mechanism: A selective, competitive antagonist of PPAR
, which plays a role in fatty acid metabolism in cancer cells.
- Clinical Efficacy: A phase 1b/2 study indicated that adding amezalpat to standard-of-care (atezolizumab + bevacizumab) improved median overall survival to 21 months compared to 15 months for the control, according to Tempest Therapeutics.
- Trial Status: A pivotal Phase 3 study (NCT06680258) to evaluate this combination as a first-line treatment is planned for 2025.
- Other Potential Uses: Preclinical data suggests potential activity in other advanced solid tumors, including renal cell carcinoma.
Disclaimer: Amezalpat is an investigational agent and is not yet approved by the FDA for widespread clinical use.
Amezalpat is an orally bioavailable, small molecule, selective and competitive antagonist of peroxisome proliferator activated receptor alpha (PPARa), with potential immunomodulating and antineoplastic activities. Upon oral administration, amezalpat targets, binds to and blocks the activity of PPARa, thereby blocking transcription of PPARa target genes leading to an intracellular metabolism shift from fatty acid oxidation (FAO) to glycolysis in FAO-dependent tumors and reducing the production of fatty acids in the tumor microenvironment (TME). As fatty acids are essential for tumor cell growth in FAO-dependent tumor cells and are needed for the metabolism of suppressive immune cells in the TME, including regulatory T-cells (Tregs), reducing the amount of fatty acids leads to a direct killing of FAO-dependent tumor cells. It also skews macrophages from the immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells, thereby stimulating an anti-tumor immune response and further killing tumor cells. Amezalpat also restores the natural inhibitor of angiogenesis thrombospondin-1 (TSP-1) and stimulator of interferon genes (STING) in the TME. PPARa, a ligand-activated nuclear transcription factor and metabolic checkpoint, regulates the expression of FAO genes and lipid metabolism. It plays a key role in immunosuppression in the TME. FAO is a metabolic pathway essential to tumor growth, survival and immunosuppression.
SYN
Example 6: 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic acid
SYN
SYN
WO2014099503 TRIAZOLONE COMPOUNDS AND USES THEREOF
Example 6: 2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1, 1′-biphenyl]-3-yl)acetic acid
Pat
WO2025235527 CRYSTALLINE FORMS OF A PPAR ALPHA ANTAGONIST
2-(3′-(3-(l-(4-(tertbutyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,T-biphenyl]-3-yl)acetic acid, depicted below as Compound A
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References
- Triazolone compounds and uses thereofPublication Number: US-2017239223-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: WO-2014099503-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: US-10568871-B2Priority Date: 2012-12-20Grant Date: 2020-02-25
- Triazolone compounds and uses thereofPublication Number: US-2024041837-A1Priority Date: 2012-12-20
- Compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and uses thereofPublication Number: BR-112015013350-B1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: US-2015344446-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: US-11666557-B2Priority Date: 2012-12-20Grant Date: 2023-06-06
- Triazolone compounds and uses thereofPublication Number: US-2020138790-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: US-9676754-B2Priority Date: 2012-12-20Grant Date: 2017-06-13
- Triazolone compounds and uses thereofPublication Number: CA-2894281-CPriority Date: 2012-12-20Grant Date: 2021-04-20
- Triazolone compounds and uses thereofPublication Number: WO-2024102620-A2Priority Date: 2022-11-09
- Triazolone compounds and uses thereofPublication Number: AU-2013363398-B2Priority Date: 2012-12-20Grant Date: 2017-06-01
- Triazolone compounds and uses thereofPublication Number: EP-2935228-B9Priority Date: 2012-12-20Grant Date: 2017-12-06
- Triazolone compounds and uses thereofPublication Number: CA-2894281-A1Priority Date: 2012-12-20
- Triazolone compounds and uses thereofPublication Number: EP-2935228-B1Priority Date: 2012-12-20Grant Date: 2017-08-02
/////////////amezalpat, ANAX LAB, antineoplastic, TPST 1120, FDA Fast Track, Orphan Drug, 1EQ4LQN9N3
Alnodesertib
Alnodesertib
CAS 2267316-76-5
MF C18H24N6O2S MW388.49
4-[4-[(cyclopropyl-methyl-oxo-λ6-sulfanylidene)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-amine
4-[4-[(cyclopropyl-methyl-oxo-lambda6-sulfanylidene)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-amine
(S)-({2-(2-aminopyridin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}imino)(cyclopropyl)(methyl)-λ6
-sulfanone
serine/threonine kinase inhibitor, antineoplastic, ART 0380, EX-A9085
Alnodesertib (formerly known as ART0380) is an investigational, orally administered drug designed to treat various types of cancer. It is a selective inhibitor of ATR (Ataxia-Telangiectasia and Rad3-related protein), a key kinase involved in DNA repair and cell cycle progression.
Mechanism of Action
Alnodesertib works by disrupting the DNA Damage Response (DDR):
- Targets ATR Kinase: It selectively inhibits ATR, which cancer cells rely on to fix DNA damage caused by rapid replication.
- Blocks Signaling: By blocking the phosphorylation of CHK1, it prevents the activation of DNA damage checkpoints.
- Induces Apoptosis: Inhibiting these repair pathways prevents cancer cells from surviving replication stress, ultimately leading to cell death (apoptosis).
Clinical Status and Indications
As of early 2026, alnodesertib is undergoing several clinical trials:
- Metastatic Colorectal Cancer (mCRC): The FDA granted Fast Track designation in September 2025 for alnodesertib in combination with irinotecan for adult patients with ATM-negative mCRC in the third-line setting.
- Ovarian Cancer: In March 2026, Artios Pharma reported that a Phase 2a study reached its primary endpoint, showing that adding a low dose of alnodesertib to gemcitabine improved progression-free survival in patients with platinum-resistant high-grade serous ovarian carcinoma (HGSOC).
- Other Solid Tumours: It is being evaluated in the ongoing STELLA Phase 1/2a study for its potential across multiple solid tumour types characterized by high replication stress.
Key Facts
| Feature | Details |
|---|---|
| Developer | Artios Pharma Limited |
| Drug Class | ATR Kinase Inhibitor |
| Administration | Oral |
| Current Phase | Phase 2 clinical trials |
| FDA Status | Fast Track Designation (for ATM-negative mCRC) |
SYN
EXAMPLES 39a and 39b
(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4- yl)imino)(cyclopropyl)(methyl)-λ6-sulfanone
and
(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4- yl)imino)(cyclopropyl)(methyl)-λ6-sulfanone
[0648] Synthesis is similar to that described for Example 24. The mixture of diastereomers (26.8 mg, 0.069 mmol) was separated by Chiral SFC (Mobile phase: n-hexane (0.1% DEA):EtOH(0.1% DEA) = 70:30; Flow rate: 80 g / min; 20 min; Column temperature: 35 °C; Back pressure: 100 bar; Column: Gilson-281, AY 20 x 250mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 39a (6.6mg, 25% yield, >99% ee) as a white solid and 39b (7.1mg, 27% yield, >99% ee) as a white solid.
[0649] 39a ((R)-cyclopropyl(methyl)-λ6-sulfanone or (S)-cyclopropyl(methyl)-λ6-sulfanone): 1H NMR (500 MHz, CD3OD) δ 8.03 – 7.91 (m, 1H), 7.53 (s, 1H), 7.49 (dd, J =5.5, 1.4 Hz, 1H), 5.97 (s, 1H), 4.48 (d, J = 4.6 Hz, 1H), 4.11 (d, J = 12.0 Hz, 1H), 4.02 (dt, J = 11.3, 3.6 Hz, 1H), 3.82 (d, J = 11.4 Hz, 1H), 3.75 (dt, J = 11.5, 3.0 Hz, 1H), 3.65 – 3.56 (m, 4H), 3.25 (tdJ, = 12.8, 3.8 Hz, 1H), 3.01 (td, J = 7.9, 4.0 Hz, 1H), 1.42 (dd, J = 10.2, 5.4 Hz, 1H), 1.31 (dt, J = 11.1, 6.2 Hz, 4H), 1.20 (dt,J = 11.3, 5.7 Hz, 2H); MS (ES+) C18H24N6O2S requires: 388, found: 389 [M+H]+; Rt = 11.35 min.
[0650] 39b ((R)-cyclopropyl(methyl)-λ6-sulfanone or (S)-cyclopropyl(methyl)-λ6-sulfanone): 1H NMR (500 MHz, CD3OD) δ 7.97 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 7.49 (dt, J = 5.5, 1.3 Hz, 1H), 5.97 (s, 1H), 4.50 (s, 1H), 4.08 (d, J = 12.7 Hz, 1H), 4.02 (dd, J = 11.4, 3.7 Hz, 1H), 3.82 (d, J = 11.3 Hz, 1H), 3.75 (dt, J = 11.4, 3.0 Hz, 1H), 3.66 – 3.55 (m, 4H), 3.25 (tdJ, = 12.9, 3.9 Hz, 1H), 3.05 – 2.97 (m, 1H), 1.41 (dt, J = 10.6, 5.2 Hz, 1H), 1.31 (dd, J = 11.8, 5.8 Hz, 4H), 1.20 (dt, J = 11.1, 5.6 Hz, 2H); MS (ES+) C18H24N6O2S requires: 388, found: 389 [M+H]+; Rt = 15.22 min.
[0651] Alternatively, Example 39a can also be prepared from Int. CC, Isomer lb.
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References
- HETEROCYCLIC INHIBITORS OF KINASE ATRPublication Number: WO-2019014618-A1Priority Date: 2017-07-13
- Heterocyclic inhibitors of ATR kinasePublication Number: US-11434233-B2Priority Date: 2017-07-13Grant Date: 2022-09-06
- Heterocyclic inhibitors of ATR kinasePublication Number: US-10800769-B2Priority Date: 2017-07-13Grant Date: 2020-10-13
- Heterocyclic inhibitors of ATR kinasePublication Number: US-10392376-B2Priority Date: 2017-07-13Grant Date: 2019-08-27
- Heterocyclic inhibitors of atr kinasePublication Number: US-2019016713-A1Priority Date: 2017-07-13
- Heterocyclic inhibitors of atr kinasePublication Number: US-2020102296-A1Priority Date: 2017-07-13
- Heterocyclic inhibitors of atr kinasePublication Number: US-2021047311-A1Priority Date: 2017-07-13
///////alnodesertib, ANAX LAB, serine/threonine kinase inhibitor, antineoplastic, ART 0380, EX-A9085
Zeprumetostat
Zeprumetostat
CAS 2098545-98-1
MF C32H44N4O4 MW 548.7 g/mol
CHINA 2025, APPROVALS 2025
- 4-Benzofurancarboxamide, N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-ethyl-6-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-2-(1-piperidinylmethyl)-
- N-[(1,2-Dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-ethyl-6-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-2-(1-piperidinylmethyl)-4-benzofurancarboxamide
N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-ethyl-6-[ethyl(oxan-4-yl)amino]-2-[(piperidin-1-yl)methyl]-1-benzofuran-4-carboxamide
enhancer of zeste homolog 2 (EZH2) inhibitor, antineoplastic, Airijing® (China), EZH2-IN-15, SHR 2554
The chemical structure for zeprumetostat was obtained from WHO proposed INN list 131 (August 2024). The INN record describes the compound as an enhancer of zeste homolog 2 (EZH2) inhibitor and antineoplastic. The chemical structure is claimed in patent WO2017084494A1 [3]. Based on Hengrui’s declared development pipeline, we predicted at that time that zeprumetostat was likely the INN for their EZH2 inhibitor clinical lead SHR2554.
Zeprumetostat is an orally available selective inhibitor of the histone lysine methyltransferase (HMT) enhancer of zeste homolog 2 (EZH2), with potential antineoplastic activity. Upon oral administration, zeprumetostat selectively targets, binds to and inhibits the activity of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 on lysine 27 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased proliferation of EZH2-expressing cancer cells. EZH2, an HMT class enzyme and the catalytic subunit of the polycomb repressive complex 2 (PRC2), is overexpressed or mutated in a variety of cancer cells and plays a key role in tumor cell proliferation; its expression is correlated with tumor initiation, progression, stem cell self-renewal, migration and angiogenesis.
Zeprumetostat is a small molecule drug. The usage of the INN stem ‘-metostat’ in the name indicates that Zeprumetostat is a histone N-methyltransferase inhibitor. Zeprumetostat has a monoisotopic molecular weight of 548.34 Da.
- Zeprumetostat, Azacitidine Combined With Lipo-MIT in R/R PTCLCTID: NCT07372352Phase: Phase 2Status: RecruitingDate: 2026-01-28
- EZH2 Inhibitor Zeprumetostat in Combination Therapy for Patients With Relapsed or Refractory Mature T-cell and NK-cell LymphomasCTID: NCT07339527Phase: Phase 1/Phase 2Status: Not yet recruitingDate: 2026-01-14
PAT
WO2017084494
[0234]N-((4,6-dimethyl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide
5-Ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxylic acid 1n (1.0 g, 2.4 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (696 mg, 3.6 mmol), 1-hydroxybenzotriazole (490 mg, 3.6 mmol), and N,N-diisopropylethylamine (1.56 g, 12.1 mmol) were added. The mixture was stirred for 1 hour, and then 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride 2a (593 mg, 3.0 mmol, prepared by the method disclosed in patent application “WO2014097041”) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, excess water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V = 8:1). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product N-((4,6-dimethyl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide 2 (750 mg, white solid), yield: 57%.
[0238]
1H NMR(400MHz,DMSO-d 6):δ11.48(s,1H),8.15(t,1H),7.39(s,1H),6.46(s,1H),5.86(s,1H),4.32(d,2H),3.83(d,2H),3.54(s,2H),3.21(t,2H),3.01-3.07(m,2H),2.92-2.97(m,1H),2.77-2.82(m,2H),2.39(brs,4H),2.23(s,3H),2.11(s,3H),1.64-1.67(brd,2H),1.47-1.55(m,6H),1.36-1.37(brd,2H),1.02(t,3H),0.82(t,3H).
PAT
WO2019091450]
The method for preparing compounds from Formula IIa to Formula Ia provided by this invention can be specifically referred to in the methods for preparing amides disclosed in PCT applications WO2017084494A, WO2012142513, WO2013039988, WO2015-141616, and WO2011140325.
In a 25 mL three-necked flask, starter IIa (50 mg, 0.12 mmol), 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (34.5 mg, 0.18 mmol), 1-hydroxybenzotriazole (23.67 mg, 0.18 mmol), and N,N-diisopropylethylamine (77.89 mg, 0.6 mmol) were mixed and dissolved in 3 mL of N,N-dimethylformamide and stirred until homogeneous. Then, starter 3-(aminomethyl)-4,6-dimethylpyridine-2(1H)-one hydrochloride (24.9 mg, 0.13 mmol) was added and the mixture was stirred at room temperature until the thin-layer chromatography showed that starter IIa had disappeared. The reaction was then terminated. Excess water was added to the reaction solution, and the mixture was extracted with a mixed solvent of dichloromethane and methanol. The organic phases were combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a dichloromethane-methanol eluent system to give 30.1 mg of white solid, yield 47.0%. [0151]m/z[M+H]
1H NMR(400MHz,DMSO-d6)ppm 11.51(s,1H)8.17(t,1H)7.39(s,1H)6.47(s,1H)5.86(s,1H)4.32(d,2H)3.83(d,2H)3.53(s,2H)3.21(t,2H)3.04(d,2H)2.94(br.s .,1H)2.79(d,2H)2.38(br.s.,4H)2.23(s,3H)2.08-2.14(m,3H)1.65(d,2H)1.44-1.56(m,6H)1.36(d,2H)1.02(t,3H)0.81(t,3H).
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References
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-11059811-B2Priority Date: 2015-11-19Grant Date: 2021-07-13
- Derived from benzofuran, method of preparing it and using it in medicinePublication Number: ES-2760510-T3Priority Date: 2015-11-19Grant Date: 2020-05-14
- Benzofuran derivative, a method for production thereof and use thereof in medicinePublication Number: RU-2727198-C2Priority Date: 2015-11-19Grant Date: 2020-07-21
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-2020354349-A1Priority Date: 2015-11-19
- BENZOFURAN DERIVATIVE, ITS USES AND ITS PREPARATION PROCESS, AND PHARMACEUTICAL COMPOSITIONPublication Number: BR-112018007876-B1Priority Date: 2015-11-19
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-2018327394-A1Priority Date: 2015-11-19
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: EP-3378859-B1Priority Date: 2015-11-19Grant Date: 2019-10-30
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: US-10759787-B2Priority Date: 2015-11-19Grant Date: 2020-09-01
- Benzofuran derivative, preparation method thereof and use thereof in medicinePublication Number: EP-3378859-A1Priority Date: 2015-11-19
- Crystal of benzofuran derivative free base and preparation methodPublication Number: US-11155537-B2Priority Date: 2017-05-18Grant Date: 2021-10-26
- Use of ezh2 inhibitor combined with btk inhibitor in preparing drug for treating tumorPublication Number: US-2021030736-A1Priority Date: 2017-05-18
- Use of EZH2 inhibitor combined with BTK inhibitor in preparing drug for treating tumorPublication Number: US-11065239-B2Priority Date: 2017-05-18Grant Date: 2021-07-20
- Crystal of benzofuran derivative free base and preparation methodPublication Number: US-2021130333-A1Priority Date: 2017-05-18
- Determination and preparation method of benzofuran derivative free basePublication Number: KR-102612379-B1Priority Date: 2017-05-18Grant Date: 2023-12-12
//////////zeprumetostat, ANAX LAB, CHINA 2025, APPROVALS 2025, antineoplastic, Airijing® (China), EZH2-IN-15, SHR 2554
Zelebrudomide
Zelebrudomide
CAS 2416131-46-7
MF C39H45N9O5 MW 719.8 g/mol
3-[4-[1-[[(3S)-1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]piperidin-4-yl]anilino]-5-piperidin-1-ylpyrazine-2-carboxamide
protein degrader, antineoplastic, NX 2127, LSC67HA8DE, NX-2127, BTK Degrader NX-2127
Zelebrudomide (NX-2127) is an investigational new drug that is being evaluated by Nurix Therapeutics for the treatment of relapsed or refractory B-cell malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Waldenström macroglobulinemia (WM). It is an orally bioavailable proteolysis targeting chimera (PROTAC) designed to degrade Bruton’s tyrosine kinase (BTK) along with the immunomodulatory proteins Ikaros (IKZF1) and Aiolos (IKZF3).[1]
- OriginatorNurix
- ClassAntineoplastics; Small molecules
- Mechanism of ActionAgammaglobulinaemia tyrosine kinase degraders; IKZF1 protein degraders; IKZF3 protein degraders
Phase IChronic lymphocytic leukaemia; Diffuse large B cell lymphoma; Follicular lymphoma; Lymphoma; Mantle-cell lymphoma; Marginal zone B-cell lymphoma; Waldenstrom’s macroglobulinaemia
- 09 Dec 2024Pharmacodynamics data from a preclinical studies in Chronic lymphocytic leukaemia released by Nurix Therapeutics
- 11 Jul 2024NX 2127 is still in phase I development in Chronic-lymphocytic-leukaemia (Late-stage disease, Second-line therapy or greater) in USA (PO) (NCT04830137)
- 11 Jul 2024NX 2127 is still in phase I development in Diffuse large B cell lymphoma(Late-stage disease, Second-line therapy or greater) in USA (PO) (NCT04830137)
Zelebrudomide, (S)- is the S-enantiomer of zelebrudomide, an orally bioavailable chimeric targeting molecule (CTM) and targeted degrader of Bruton’s tyrosine kinase (BTK), with potential immunomodulatory drug (IMiD) and antineoplastic activities. Zelebrudomide is comprised of a cereblon (CRBN)-binding moiety conjugated, via a linker, to a BTK-binding moiety. Upon administration, zelebrudomide targets and binds to BTK with its BTK-targeting moiety. Upon binding, the CRBN-binding moiety recruits CRBN, a component of the CRL4-CRBN E3 ubiquitin ligase complex. This catalyzes ubiquitination and proteasome-mediated degradation of BTK, and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B-cells that overexpress BTK. In addition, zelebrudomide catalyzes the degradation of CRBN neosubstrates Aiolos (IKZF3) and Ikaros (IKZF1), two transcription factors regulating T-cell function. This modulates the activity of the immune system and increases the activation of T-lymphocytes, thereby increasing T-cell-mediated anti-tumor effects. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival. CRBN, the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex, plays a key role in the ubiquitination of certain proteins. Compared to BTK inhibitors, zelebrudomide may overcome tumor resistance associated with BTK inhibitor-induced resistance mutations.
A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies
CTID: NCT04830137
Phase: Phase 1
Status: Recruiting
Date: 2025-03-13
REF
- Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton’s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell MalignanciesPublication Name: Journal of Medicinal ChemistryPublication Date: 2024-02-01PMID: 38300987DOI: 10.1021/acs.jmedchem.3c01007
- The IUPHAR Guide to Immunopharmacology: connecting immunology and pharmacologyPublication Name: ImmunologyPublication Date: 2020-03-02PMCID: PMC7160657PMID: 32020584DOI: 10.1111/imm.13175
- Effect of osmotic pressure, ionic strength and dibutyryl cyclic adenosine monophosphate on the adhesion of hen erythrocytesPublication Name: Blut Zeitschrift für die gesamte BlutforschungPublication Date: 1976-07PMID: 10025DOI: 10.1007/bf01005212
SYN
compound 28 Journal of Medicinal ChemistryPublication Date: 2024-02-01PMID: 38300987DOI: 10.1021/acs.jmedchem.3c01007
SYN
WO2021219070A1
PAT
PAT
- Bifunctional compounds for degrading btk via ubiquitin proteosome pathwayPublication Number: US-2023227471-A1Priority Date: 2019-12-04
- Bifunctional compounds for degrading btk via ubiquitin proteosome pathwayPublication Number: WO-2021113557-A1Priority Date: 2019-12-04
- Bifunctional compounds for degrading btk via ubiquitin proteosome pathwayPublication Number: US-2023029378-A1Priority Date: 2018-10-15
- Bifunctional compounds for degrading btk via ubiquitin proteosome pathwayPublication Number: WO-2020081450-A1Priority Date: 2018-10-15
- Bifunctional compounds for degrading BTK via ubiquitin proteosome pathwayPublication Number: US-11479556-B1Priority Date: 2018-10-15Grant Date: 2022-10-25
- Btk reducing molecules for treatment of cancers and immune system disordersPublication Number: WO-2023235691-A1Priority Date: 2022-05-31
- Piperidinylpyrazine-carboxamide compounds for treating and preventing cancer and for degrading btkPublication Number: US-2023149416-A1Priority Date: 2021-10-26
- Piperidinylpyrazine-carboxamide compounds for treating and preventing cancer and for degrading btkPublication Number: WO-2023076303-A1Priority Date: 2021-10-26
- Bifunctional compounds for degrading BTK via ubiquitin proteosome pathwayPublication Number: US-11820781-B2Priority Date: 2019-12-04Grant Date: 2023-11-21
- Bifunctional compounds for degrading btk via ubiquitin proteosome pathwayPublication Number: US-2021198280-A1Priority Date: 2019-12-04
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References
References
- Salvaris RT, Brennan J, Lewis KL (February 2025). “BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL”. Cancers. 17 (3): 557. doi:10.3390/cancers17030557. PMC 11817010. PMID 39941922.
| Clinical data | |
|---|---|
| Other names | NX-2127 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2416131-46-7 |
| PubChem CID | 146559796 |
| ChemSpider | 128922006 |
| UNII | LSC67HA8DE |
| Chemical and physical data | |
| Formula | C39H45N9O5 |
| Molar mass | 719.847 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
//////////zelebrudomide, anax lab, protein degrader, antineoplastic, NX 2127, LSC67HA8DE, NX-2127, BTK Degrader NX-2127
Veonetinib
Veonetinib
👉CAS 1210828-09-3
MF C27H28FN3O4 MW 477.5 g/mol
5-[2-[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxyethyl]-5-azaspiro[2.4]heptan-7-ol
5-AZASPIRO(2.4)HEPTAN-7-OL, 5-(2-((4-((4-FLUORO-2-METHYL-1H-INDOL-5-YL)OXY)-6-METHOXY-7-QUINOLINYL)OXY)ETHYL)-
5-(2-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol
(7RS)-5-[2-({4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin7-yl}oxy)ethyl]-5-azaspiro[2.4]heptan-7-ol
tyrosine kinase inhibitor, antineoplastic, U7PA8S6XGJ
👉SYN
Example 3
5-(2-(4-(4-fluoro-2-methyl-lH-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol
The above product from Example 2 (75 mg) was dissolved into MeOH (8 ml) and stirred at RT.
NaBH4 (75 mg) was added to the reaction and stirred at RT for 30 min. The reaction was evaporated and purified by column chromatography to give title compound (60 mg). Mass: (M + 1), 478
Patent Scope
- Covers:
- Quinoline–indole kinase inhibitors
- VEGFR / angiogenesis targets
- Broad Markush structures
Fragment A: Indole Phenol
4-fluoro-2-methyl-1H-indol-5-ol
Typical Preparation
- Fischer indole synthesis or substituted aniline cyclization
- Fluorination / directed substitution
- Hydroxyl introduction at C-5
Fragment B: Quinoline Electrophile
4-chloro-6-methoxy-7-(leaving group) quinoline
Typical Route
- Start from 6-methoxyaniline
- Skraup / Doebner–Miller → quinoline core
- Chlorination at C-4
- Functionalization at C-7 (OH or halide)
Fragment C: Chiral Spiro Amine
(R)-5-azaspiro[2.4]heptan-7-ol
- Usually from:
- Chiral pool OR
- Resolution of racemate
- Important: defines final stereochemistry
4. STEP-BY-STEP SYNTHESIS (PATENT-ALIGNED)
Step 1: Indole–Quinoline Ether Formation
Reaction: SNAr / Ullmann-type coupling
Indole phenol + 4-chloroquinoline → aryl ether
Conditions
- Base: K2CO3 / Cs2CO3
- Solvent: DMF / DMSO
- Temp: 80–120°C
Forms:
Indole–O–quinoline core
Step 2: Introduction of Linker (C-7 substitution)
If quinoline has OH:
Quinoline–OH + Br–CH2–CH2–X → O–CH2CH2–X
If halide:Direct alkylation
Conditions
- Base: NaH / K2CO3
- Solvent: DMF
- Temp: 50–90°C
Product:
Quinoline–O–CH2CH2–X
Step 3: Coupling with Spiro Amine
Quinoline–O–CH2CH2–X + spiro amine → final amine linkage
Reaction Type
- SN2 substitution
Conditions
- Base: DIPEA / Et3N
- Solvent: ACN / DMF
- Temp: 50–80°C
Step 4: Final Deprotection / Purification
- Remove protecting groups (if any)
- Chiral purity control
- Crystallization
Step 1: Preparation of Indole–Quinoline Ether
Starting materials:
- 4-fluoro-2-methyl-1H-indol-5-ol
→ 1.00 equiv (e.g., 5.0 g, ~30 mmol) - 4-chloro-6-methoxyquinoline
→ 1.10 equiv (~33 mmol)
Reagents:
- Potassium carbonate (K₂CO₃) → 2.0 equiv (~60 mmol)
- Solvent: DMF (50–60 mL)
Procedure:
- Charge indole phenol and K₂CO₃ in DMF under nitrogen.
- Add 4-chloroquinoline portionwise.
- Heat to 100–110°C.
- Stir for 8–12 h.
Workup:
- Cool to RT
- Pour into water (200 mL)
- Extract with EtOAc (3×)
- Wash with brine, dry (Na₂SO₄)
- Concentrate
Purification:
- Silica gel chromatography (EtOAc/hexane)
Yield: ~70–80%
Product: Indole–quinoline ether intermediate
Step 2: Installation of Ethylene Linker
Starting material: Step 1 product (~25 mmol)
Reagents:
- 1,2-dibromoethane → 1.5–2.0 equiv
- Base: K₂CO₃ → 2 equiv
- Solvent: DMF (40 mL)
Procedure:
- Dissolve intermediate in DMF
- Add K₂CO₃
- Add dibromoethane
- Heat to 80–90°C for 6–8 h
Workup:
- Pour into water
- Extract with EtOAc
- Dry and concentrate
Product: Quinoline–O–CH₂CH₂–Br
Yield: ~65–75%
Step 3: Coupling with Chiral Spiro Amine
Starting materials:
- Bromo intermediate → 1.0 equiv (~15–20 mmol)
- (R)-5-azaspiro[2.4]heptan-7-ol → 1.2 equiv
Reagents:
- DIPEA or Et₃N → 2 equiv
- Solvent: Acetonitrile or DMF (30–40 mL)
Procedure:
- Combine bromo intermediate and amine in solvent
- Add DIPEA
- Heat to 60–70°C
- Stir 12–16 h
Workup:
- Remove solvent
- Dissolve in EtOAc
- Wash with water + brine
- Dry and concentrate
Yield: ~70–85%
Step 4: Final Purification
Purification options:
- Silica chromatography OR
- Recrystallization (EtOAc/hexane or IPA)
Optional:
- Convert to pharmaceutically acceptable salt
Final Yield (overall): ~35–45%
PAT
EXAMPLE 1
4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(5,8-Dioxa-10-azadispiro[2.0.4.3]-undecane)ethoxy]quinoline
Preparation of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline
Method A:
Method B:
Preparation of Title Compound
Method C:
Method D:
EXAMPLE 2
5-(2-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-one
EXAMPLE 3
5-(2-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol
PAT
PAT
CN201710900497.6 CN201610649732.2 → leads to US10689361B2
PAT
- Compounds as kinase inhibitorsPublication Number: CA-2733250-CPriority Date: 2008-08-19Grant Date: 2016-06-21
- Compounds that act as kinase inhibitorsPublication Number: ES-2617678-T3Priority Date: 2008-08-19Grant Date: 2017-06-19
- Compounds as kinase inhibitorsPublication Number: WO-2010021918-A1Priority Date: 2008-08-19
- Compounds as kinase inhibitorsPublication Number: EP-2312950-A1Priority Date: 2008-08-19
- Compounds as kinase inhibitorsPublication Number: US-8211911-B2Priority Date: 2008-08-19Grant Date: 2012-07-03
- Compounds as kinase inhibitorsPublication Number: JP-2012500269-APriority Date: 2008-08-19
- Compounds as kinase inhibitorsPublication Number: KR-20110044749-APriority Date: 2008-08-19
- Compounds as kinase inhibitorsPublication Number: EP-2312950-B1Priority Date: 2008-08-19Grant Date: 2016-11-30
- Biological activities of 5-(2-(4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol crystalline, phosphoric acid salt and its enantiomersPublication Number: US-2023399313-A1Priority Date: 2022-06-10
- Btological activities of 5-(2-(4-(4-fluoro-2-methyl-1h-indol-5- yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan- 7-ol crystalline, phosphoric acid salt and its enantiomersPublication Number: WO-2023239945-A1Priority Date: 2022-06-10
- Btological activities of 5-(2-(4-(4-fluoro-2-methyl-1h-indol-5- yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan- 7-ol crystalline, phosphoric acid salt and its enantiomersPublication Number: EP-4536652-A1Priority Date: 2022-06-10
- Compounds as kinase inhibitorsPublication Number: CA-2733250-A1Priority Date: 2008-08-19
- Compounds As Kinase InhibitorsPublication Number: US-2010048599-A1Priority Date: 2008-08-19
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REF
//////////veonetinib, ANAX LAB, tyrosine kinase inhibitor, antineoplastic, U7PA8S6XGJ
Soxataltinib
Soxataltinib
CAS 2546116-88-3
MF C29H30N8O2 MW 522.60
6-(3-hydroxy-3-methylazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
| Pyrazolo[1,5-a]pyridine-3-carbonitrile, 6-(3-hydroxy-3-methyl-1-azetidinyl)-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]hept-3-yl]-3-pyridinyl]- |
6-(3-hydroxy-3-methylazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
RET-kinase inhibitor, antineoplastic, HS-10365, HS 10365, AZ4Q643U3D
Soxataltinib (example 7) is a potent inhibitor of RET-kinase , with the IC 50of 0.601 nM. Soxataltinib plays an important role in
cancer research.
Discovery and Development
- Soxataltinib corresponds to Example 114 in a patent [WO2020228756]describing pyrazolo[1,5-a]pyridine carbonitrile RET inhibitors.
- It is believed to correspond to HS-10365, a RET inhibitor developed by Hansoh Pharma (structure disclosed via patent).
Drug class comparison:
| Drug | Company | Type |
|---|---|---|
| Selpercatinib | Eli Lilly | 1st-gen selective RET inhibitor |
| Pralsetinib | Blueprint | selective RET inhibitor |
| Soxataltinib | Hansoh | next-gen RET inhibitor |
Patent Family (Major Members)
Typical family members include:
| Patent | Jurisdiction |
|---|---|
| WO2020228756 | WIPO |
| CN112209925 | China |
| US continuation filings | USA |
| EP equivalents | Europe |
One Chinese patent describes the preparation of piperazine-containing pyrazolopyridine RET inhibitors, including Soxataltinib analogues
SYN
SYN
Example 32
| To a 25 mL sealed tube were added successively 49 (52 mg, 0.1 mmol), Pd 2(dba) 3 (5.5 mg, 0.006 mmol), t-BuXPhos (8.4 mg, 0.02 mmol), 3-methyl-3-azetidinol (26 mg, 0.3 mmol), Cs 2CO 3 (65 mg, 0.2 mmol), 1,4-dioxane (3 mL) and DMF (1 mL). The mixture was stirred at 80° C. overnight under Ar, and TLC monitoring showed no starting material 49 remained. The mixture was cooled to room temperature, and 10 mL of water was added. The mixture was stirred for 10 min, and a yellow solid precipitated. The solid was collected by filtration, dried and purified by column chromatography to give product 86 (34 mg, 65% yield). |
SYN
[1913]6-(3-hydroxy-3-methylacetidin-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile
Using 3-methylacetidin-3-ol as a raw material, in the first step of Reference Example 110, 6-(3-hydroxy-3-methylacetidin-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile was obtained.
[1916]MS m/z(ESI):523.3[M+H]
[1917]
1H NMR(400MHz,CDCl 3)δ8.40(s,1H),8.15(s,3H),7.82(d,J＝7.4Hz,1H),7.74(s,1H),6.80(d,J＝8.4Hz,1H),6.75(d,J＝1.7Hz,1H),6.72(d,J＝8.8Hz,1H),4.21(s,2H),4.01(s,2H),3.93-3.92(m,7H),3.84(d,J＝7.3Hz,4H),1.68(s,3H).
PAT
- Inhibitor containing dihecyclic derivatives, its preparation method and applicationPublication Number: CN-112368283-BPriority Date: 2019-05-14Grant Date: 2023-02-17
- Inhibitor containing dihecyclic derivatives, its preparation method and applicationPublication Number: CN-115974897-APriority Date: 2019-05-14
- Inhibitor containing dihecyclic derivatives, its preparation method and applicationPublication Number: CN-116444515-APriority Date: 2019-05-14
- Inhibitor containing bicyclic derivative, preparation method therefor and use thereofPublication Number: WO-2020228756-A1Priority Date: 2019-05-14
- Inhibitor containing bicyclic derivative, preparation method therefor and use thereofPublication Number: EP-3971187-B1Priority Date: 2019-05-14Grant Date: 2025-05-07
- Ret selective inhibitor, preparation method therefor and use thereofPublication Number: WO-2021008455-A1Priority Date: 2019-07-12
- RET selective inhibitor and preparation method and use thereofPublication Number: CN-112209925-APriority Date: 2019-07-12
- RET selective inhibitors and methods for their preparation and usePublication Number: KR-102735956-B1Priority Date: 2019-07-12Grant Date: 2024-11-28
- RET selective inhibitors and preparation methods and uses thereofPublication Number: CN-114072404-BPriority Date: 2019-07-12Grant Date: 2023-09-15
- Inhibitor containing bicyclic derivative, preparation method therefor and use thereofPublication Number: US-2022259201-A1Priority Date: 2019-05-14
- Heteroaromatic ring compound as ret kinase inhibitor, and preparation and use thereofPublication Number: US-2023322769-A1Priority Date: 2020-08-20
- 3,6 diazabicyclo[3.1.1]heptane derivatives as RET kinase inhibitorsPublication Number: CN-112778337-BPriority Date: 2019-11-08Grant Date: 2023-09-26
- Ret selective inhibitor, preparation method therefor and use thereofPublication Number: EP-3998265-A1Priority Date: 2019-07-12
- RET selective inhibitor and preparation method and use thereofPublication Number: CN-117865952-APriority Date: 2019-07-12
- Ret selective inhibitor, preparation method therefor and use thereofPublication Number: US-2022289740-A1Priority Date: 2019-07-12
- Crystal form of free base of inhibitor containing bicyclic ring derivative and preparation method and application of crystal formPublication Number: US-2023406865-A1Priority Date: 2020-11-13
- Crystal form of free base of inhibitor containing bicyclic ring derivative and preparation method and application of crystal formPublication Number: EP-4245757-A1Priority Date: 2020-11-13
- Crystal form of free base of inhibitor containing bicyclic ring derivative and preparation method and application of crystal formPublication Number: WO-2022100738-A1Priority Date: 2020-11-13
- Crystal form of inhibitor free base including bicyclic derivatives, preparation method and use thereofPublication Number: KR-20230107271-APriority Date: 2020-11-13
- Heteroaromatic ring compound as ret kinase inhibitor, and preparation and use thereofPublication Number: EP-4201936-A1Priority Date: 2020-08-20
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#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma
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/////////soxataltinib, ANAX, RET-kinase inhibitor, antineoplastic, HS-10365, HS 10365, AZ4Q643U3D
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Ranosidenib
Ranosidenib
CAS 2301974-60-5
MF C15H16F9N5O MW 453.31 g/mol
(1S)-3-[4,6-bis[[(2R)-1,1,1-trifluoropropan-2-yl]amino]-1,3,5-triazin-2-yl]-2,6,6-trifluorocyclohex-2-en-1-ol
(1S)-3-(4,6-bis{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol
isocitrate dehydrogenase (IDH) inhibitor, antineoplastic, [14C] HMPL-306, HMPL 306, PC64OXS2C2
- OriginatorHutchison MediPharma
- DeveloperHUTCHMED
- ClassAntineoplastics; Small molecules
- Mechanism of ActionIsocitrate dehydrogenase 1 inhibitors; Isocitrate dehydrogenase 2 inhibitors
- Phase IIIAcute myeloid leukaemia
- No development reportedHaematological malignancies; Solid tumours
- 28 Sep 2025No recent reports of development identified for phase-I development in Haematological-malignancies(Late-stage disease, Second-line therapy or greater) in Spain (PO)
- 28 Sep 2025No recent reports of development identified for phase-I development in Haematological-malignancies(Late-stage disease, Second-line therapy or greater) in USA (PO)
- 19 Sep 2025No development reported – Phase-I for Solid tumours (Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA (PO)
Ranosidenib is a small molecule drug. Ranosidenib is under investigation in clinical trial NCT06387069 (A Study to Evaluate HMPL-306 in Patients With IDH1- and IDH2-mutated Acute Myeloid Leukemia). Ranosidenib has a monoisotopic molecular weight of 453.12 Da.
Ranosidenib is an orally bioavailable inhibitor of mutated forms of both isocitrate dehydrogenase type 1 (IDH1, IDH1 [NADP+] soluble) in the cytoplasm and type 2 (IDH2, isocitrate dehydrogenase [NADP+], mitochondrial) in the mitochondria, with potential antineoplastic activity. Upon administration, ranosidenib specifically targets and inhibits mutant forms of IDH1 and IDH2, thereby inhibiting the formation of the oncometabolite 2-hydroxyglutarate (2HG) from alpha-ketoglutarate (a-KG). This prevents 2HG-mediated signaling and leads to both an induction of cellular differentiation and an inhibition of cellular proliferation in tumor cells expressing IDH mutations. IDH1 and 2, metabolic enzymes that catalyze the conversion of isocitrate into a-KG, play key roles in energy production and are mutated in a variety of cancer cell types. Mutant forms of IDH1 and 2 catalyze the formation of 2HG and drive cancer growth by blocking cellular differentiation and inducing cellular proliferation.
A Study of HMPL-306 in Advanced Hematological Malignancies With mIDHCTID: NCT04764474Phase: Phase 1Status: TerminatedDate: 2026-01-29
A Study of HMPL-306 in Advanced Solid Tumors With IDH MutationsCTID: NCT04762602Phase: Phase 1Status: TerminatedDate: 2025-09-16
A Study to Evaluate HMPL-306 in Patients With IDH1or IDH2-mutated Acute Myeloid LeukemiaCTID: NCT06387069Phase: Phase 3Status: RecruitingDate: 2025-08-14
Phase I Study of HMPL-306 for the Treatment of Gliomas With IDH1 and/or IDH2 MutationsCTID: NCT07025018Phase: Phase 1Status: RecruitingDate: 2025-08-01
A Study of HMPL-306 in Patients With IDH1 and/or IDH2 Mutation of Relapsed/Refractory Myeloid Leukemia/NeoplasmsCTID: NCT04272957Phase: Phase 1Status: Unknown statusDate: 2020-06-16
SYN
https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00625
aReagents and conditions: (i) Na2PdCl4, DTBPPS, K2CO3, MeCN, H2O, 60 ℃; (ii) TBSOTf, Et3N,
DCM, 0~5 ℃; Selectfluor®, MeCN, 0~5 ℃; (iii) TBSOTf, Et3N, DCM, 0~5 ℃; Selectfluor®,
MeCN, 0~5 ℃; (iv) NaBH4, CeCl3·7H2O, EtOH, 0 ℃; (v) SFC separation.
Pat
Cycloolefin substituted heteroaromatic compounds and their use
Publication Number: US-2021363115-A2
Priority Date: 2017-09-07
PAT
Intermediate I-3
6-Chloro-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
At 0° C., to a flask were added 1,4-dioxane (50 mL), 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmo), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (2.99 g, 20 mmol) and DIEA (5.17 g, 40 mmol). The reaction was heated to 60° C. and stirred for 4 hours. After the reaction was completed, the mixture was condensed and purified by flash column chromatography (eluting with gradient water/MeOH=100:0-0:100) to give Intermediate I-3 as yellow solid (2.50 g, yield: 74%). MS (m/z): 338.0 [M+H] +
Compounds 197 and 198
3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol, optically pure diastereoisomers
| The Compound 196 was resolved by chiral HPLC to provide a pair of optically pure diastereoisomers, Compounds 197 and 198 (Chiral HPLC conditions: Preparation instrument: Shimadzu LC-10AD vp; Column: Daicel AD-H(250 mm*30 mm, 5 um); mobile phase: n-heptane/isopropanol=90/10; flow rate: 40 mL/min; column temperature: 40° C.). The first eluent (RT=4.203 min) was concentrated and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give a compound named as Compound 197, de %=99.27%, MS (m/z): 454.1 [M+1] +. The second eluent (RT=5.906 min) was concentrated and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give a compound named as Compound 198, de %=97.82%, MS (m/z): 454.2 [M+1] +. |
| Compound 197: 1H NMR (400 MHz, CD 3OD): δ 5.00-4.86 (m, 2H), 4.36-4.17 (m, 1H), 2.80-2.65 (m, 1H), 2.58-2.42 (m, 1H), 2.25-2.05 (m, 2H), 1.37-1.31 (m, 6H). |
| Compound 198: 1H NMR (400 MHz, CD 3OD): δ 5.00-4.86 (m, 2H), 4.36-4.17 (m, 1H), 2.80-2.65 (m, 1H), 2.58-2.42 (m, 1H), 2.25-2.05 (m, 2H), 1.37-1.31 (m, 6H). |
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/////////ranosidenib, isocitrate dehydrogenase (IDH) inhibitor, antineoplastic, [14C] HMPL-306, HMPL 306, PC64OXS2C2
Lead (212Pb) bamzireotide navoxetan
Lead (212Pb) bamzireotide navoxetan
CAS 2941523-47-1
MF C72H104N16O20212PbS2 MW1789.8 g/mol
2-[4-[2-[2-[2-[3-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxopropoxy]ethoxy]ethylamino]-2-oxoethyl]-10-(2-amino-2-oxoethyl)-7-(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lead-212(2+)
ANTINEOPLASTIC, D2A42X3LCS
SYN
US 11037690 B2
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///////////lead (212Pb) bamzireotide navoxetan, ANTINEOPLASTIC, D2A42X3LCS
Pebezertinib
Pebezertinib
CAS 2769954-39-2
MF C24H19F4N7O MW 497.4 g/mol
N-[4-fluoro-3-[[2-[(1-methylpyrazol-4-yl)amino]-5-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]amino]phenyl]prop-2-enamide
N-[4-fluoro-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)phenyl]prop-2-enamide
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, antineoplastic, BLU 451, BLU 203139, G8G5AU5GLJ, LNG 451
Pebezertinib is a small molecule drug. The usage of the INN stem ‘-ertinib’ in the name indicates that Pebezertinib is a epidermal growth factor receptor (EGFR) inhibitor. Pebezertinib is under investigation in clinical trial NCT05241873 ((Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations). Pebezertinib has a monoisotopic molecular weight of 497.16 Da.
Pebezertinib is an orally bioavailable, central nervous system (CNS) penetrating, mutant-selective covalent inhibitor of epidermal growth factor receptor (EGFR) exon 20 insertion (Ex20ins) activating mutations, with potential antineoplastic activity. Upon oral administration, pebezertinib selectively targets, irreversibly binds to and inhibits the activity of EGFR Ex20ins and some other oncogenic point mutations. This prevents EGFR Ex20ins-mediated signaling. This may induce cell death and inhibit tumor growth in EGFR Ex20ins-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumors, plays a key role in tumor cell proliferation and tumor vascularization. Pebezertinib is able to penetrate the blood-brain-barrier (BBB) and may therefore exert its activity against EGFR Ex20ins-driven CNS primary tumors and CNS metastases. Pebezertinib does not inhibit the activity of wild-type (WT) EGFR. EGFR Ex20ins are oncogenic driver mutations that constitutively upregulate kinase activity.
(Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations
CTID: NCT05241873
Phase: Phase 1
Status: Terminated
Date: 2025-02-10
Conditions: Lung Neoplasm Malignant; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Disease; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms by Histologic Type; EGFR Exon 20 Mutation; EGFR Exon 20 Insertion Mutation; EGFR Activating Mutation; Antineoplastic Agents; Metastatic Lung Cancer; Brain Metastases; EGFR-mutated NSCLC; EGFR Atypical Mutations, Including G719X and L861Q
Interventions: Pemetrexed
Linked Compound CID: 426756; 135410875; 10339178; 163280903
SYN
Scheme 21: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 37):
Step 1: Synthesis of 5-bromo-2-chloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (89):
[0286] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure A. The crude was purified by combiflash eluted with 40% ethyl acetate in hexane to get (89) as pale yellow solid (1.3 g, Yield: 44.24 %). MS: [M+H]+ 346.97.
Step 2: Synthesis of 2-chloro-N-(2-fluoro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine (91):
[0287] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M3. The crude was purified by combiflash eluted with 35% ethyl acetate in hexane to get desired product (91) as light yellow solid (700 mg; Yield: 50.12%). MS:
[M+H]+ 413.10
Step 3: Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (92):
[0288] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure H. The crude was purified by combiflash eluted with 1% methanol in dichloromethane to get desired product (92) as pale yellow solid (500 mg; Yield: 70.24%). MS:
[M+H]+ 474.09
Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (93):
[0289] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L to get (93) as semi solid (350 mg; Yield: 74.78%). MS: [M+H]+ 444.11
Step 5: Synthesis of N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 37):
[0290] Title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K. The crude was purified by Prep HPLC to get Compound 37 as off white solid (30 mg, Yield: 13.33%).1H NMR (400 MHz, DMSO-d6): δ 10.21 (bs, 1H), 9.24 (bs, 1H), 8.53 (bs, 1H), 7.99 (s, 1H), 7.71-7.81 (m, 5H), 7.57 (s, 1H), 7.08-7.16 (m, 3H), 6.37-6.44 (m, 1H), 6.21-6.26 (m, 1H), 5.74 (d, J = 8.4 Hz, 1H), 3.54 (s, 3H). LCMS: [M+H]+ 498.35.
SYN
International Patent Application No. PCT/US2021/057472, the entire teachings of which are incorporated herein by reference, discloses selective inhibitors of EGFR, including exon 20 mutant proteins, which can be used to treat various cancers. The structure of one of the inhibitors disclosed in PCT Patent Application No. PCT/US2021/057472, referred to
herein as “Compound (I)” is shown below:
Example 1 : Preparation of Compound (I)
Synthesis of N-(4-fluoro-3-((2-((l-methyl-lH-pyrazol-4-yl)amino)-5-(4-(trifluoro methyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound I):
Step 1 : Synthesis of 5-bromo-2-chloro-N-(2-fluoro-5-nitrophenyl)pyrimidin-4-amine (89):
To an ice cold solution of 2-fluoro-5-nitroaniline (12) (1.0 eq) in tetrahydrofuran was added sodium hydride (60% dispersion in mineral oil, 3.0 eq) portion-wise. The resulting reaction mixture was stirred at room temperature for 30 minutes and followed by the addition of 2, 4-di chi oro-5 -bromopyrimidine (88) (1.0 eq). The resulting reaction mixture was heated at 60 °C for 16 hours. After completion (TLC monitoring), quenched with ice, extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by combiflash eluted with 40% ethyl acetate in hexane to get (89) as pale yellow solid (1.3 g, Yield: 44.24 %). MS: [M+H]+ 346.97.
Step 2: Synthesis of 2-chloro-N-(2-fluoro-5-nitrophenyl)-5-(4-(trifluoromethyl)phenyl) pyrimidin-4-amine (91):
To a solution of halo derivative (89) (1.0 eq) and respective boronate acid/ester derivative (90) (1.1 eq) in A A i methyl form am ide: water (4: 1) was added sodium carbonate or sodium bicarbonate (2.0 eq). The resulting reaction mixture was degassed under argon atmosphere for 15 minutes, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.1 eq). The resulting reaction mixture was heated at 90 °C for 16 hours. After completion of reaction (TLC monitoring), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by combiflash eluted with 35% ethyl acetate in hexane to get desired product (91) as light yellow solid (700 mg; Yield: 50.12%). MS: [M+H]+413.10.
Step 3 : Synthesis of N4-(2-fluoro-5-nitrophenyl)-N2-(l-methyl-lH-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (92):
To an ice-cold solution of chloro compound (91) (1.0 eq) in isopropanol was added amine (22) (1.2 eq) and trifluoroacetic acid (2.0 eq). The reaction mixture was heated at 110 °C for 16 hours. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure, added saturated solution of sodium bicarbonate and extracted with dichloromethane (3 times). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude was purified by combiflash eluted with 1% methanol in di chloromethane to get desired product (92) as pale yellow solid (500 mg; Yield: 70.24%). MS: [M+H]+ 474.09.
Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-N2-(l-methyl-lH-pyrazol-4-yl)-5-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (93):
To an ice cold solution of nitro derivative (92) (1.0 eq) in methanol: tetrahydrofuran: water (2:2: 1) were added zinc-dust or iron powder (5 eq) and ammonium chloride (5 eq). The resultant reaction mixture was stirred at room temperature for 2 hours. After completion of reaction (TLC monitoring), reaction mixture passed through celite bed washed with 5% methanol in dichloromethane. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to get the desired product (93) as semi solid (350 mg; Yield: 74.78%). MS: [M+H]+ 444.11.
Step 5 : Synthesis of N-(4-fluoro-3-((2-((l-methyl-lH-pyrazol-4-yl)amino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound I):
To a solution of amino compound (93) (1.0 eq) in dichloromethane: tetrahydrofuran (1 :1) was cooled to -40 °C followed by triethylamine (3-5 eq) and acryloyl chloride (1.0 eq) were added. The mixture was stirred at the same temperature for 2 hours. After completion of reaction (monitored by TLC), added water and extracted with dichloromethane (3 times). The combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crudes were purified by Prep-HPLC purification to to obtain Compound I as off white solid (30 mg, Yield: 13.33%). ‘H NMR (400 MHz, DMSO-de): 8 10.21 (bs, 1H), 9.24 (bs, 1H), 8.53 (bs, 1H), 7.99 (s, 1H), 7.71-7.81 (m, 5H), 7.57 (s, 1H), 7.08-7.16 (m, 3H), 6.37-6.44 (m, 1H), 6.21-6.26 (m, 1H), 5.74 (d, J= 8.4 Hz, 1H), 3.54 (s, 3H). LCMS: [M+H]+ 498.35.
PAT
- Pyrimidine compounds, compositions, and medicinal applications thereofPublication Number: WO-2022094354-A1Priority Date: 2020-10-30Linked Compounds: 1,056Linked Substances: 1,365
- Pyrimidine compounds, compositions and pharmaceutical uses thereofPublication Number: CN-116685583-APriority Date: 2020-10-30Linked Compounds: 921Linked Substances: 1,108
- Pyrimidine compounds, compositions, and medicinal applications thereofPublication Number: TW-202233603-APriority Date: 2020-10-30Linked Compounds: 531Linked Substances: 575
- Pyrimidine compounds, compositions, and their medicinal applicationsPublication Number: KR-20230116795-APriority Date: 2020-10-30Linked Compounds: 699Linked Substances: 744
- Egfr inhibitors for treatment of cancerPublication Number: WO-2024097270-A1Patent Family: TW-202432143-A; WO-2024097270-A1Priority Date: 2022-11-01Inventor(s): ANKROM WENDY; MAR BRENTON; PANDEY ANJALI; PEARSON PAUL; ZALUTSKAYA ALENAAssignee(s): BLUEPRINT MEDICINES CORPClassification: A61K31/506; A61K31/519; A61K31/555; A61P35/00; A61P35/04Abstract: The present disclosure provides improved methods of treating non-small cell lung cancer characterized by EGFR mutation using Compound (I): or a pharmaceutically acceptable salt thereof.Linked Compounds: 27Linked Substances: 28
- Salt and crystal forms of an epidermal growth factor receptor inhibitorPublication Number: US-2025282761-A1Patent Family: AU-2023265064-A1; CN-119923392-A; EP-4519254-A1; IL-316663-A; JP-2025517634-A; KR-20250012078-A; MX-2024013485-A; TW-202409016-A; US-2025282761-A1; WO-2023215431-A1Priority Date: 2022-05-04Inventor(s): GRUFF ERIC; Kuang Shanming; PANDEY ANJALI; SHAH HARSH; XIE TIANAssignee(s): BLUEPRINT MEDICINES CORPClassification: A61K31/506; C07D403/12Abstract: Various salt forms and free base solid forms of Compound (I) represented by the following formula are disclosed. Pharmaceutical compositions comprising the same, methods of treating a disease associated with an epidermal growth factor receptor (EGFR) family kinase using the same, and methods for making the salt forms of Compound (I) and crystalline forms thereof are also disclosed.Linked Compounds: 11Linked Substances: 13
- Salt and crystal forms of an epidermal growth factor receptor inhibitorPublication Number: WO-2023215431-A1Priority Date: 2022-05-04Linked Compounds: 18Linked Substances: 22
- Salt and crystal forms of an epidermal growth factor receptor inhibitorPublication Number: EP-4519254-A1Priority Date: 2022-05-04Linked Compounds: 14Linked Substances: 16
- Pyrimidine compounds, compositions, and medicinal applications thereofPublication Number: EP-4237418-A1Priority Date: 2020-10-30Linked Compounds: 821Linked Substances: 918
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[1].
Zhou Y, et al., Anti-PD-1/L1 antibody plus anti-VEGF antibody vs. more VEGFR-targeted TKI as first-line therapy for unresectable hepatocellular carcinoma: a network meta-analysis. Explor Target Antitumor Ther. 2024;5(3):568-580. [Content Brief]
//////////pebezertinib, antineoplastic, BLU 451, BLU 203139, G8G5AU5GLJ, LNG 451
Orenasitecan
Orenasitecan
CAS 2418533-89-6
MF C72H86N12O20S MW1471.59
(3S)-3-[3-[2-[2-[2-[[4-[[(1R)-2-carboxy-1-[3-[[3-(propylcarbamoylamino)phenyl]sulfonylamino]phenyl]ethyl]carbamoylamino]phenyl]carbamoylamino]ethoxy]ethoxy]ethoxy]propanoylamino]-4-[(2S)-2-[[(2S)-1-[[(19S)-10,19-diethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-19-yl]oxy]-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-oxobutanoic acid
(4S)-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1Hpyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl N-{1-[4-({[(1R)-2-
carboxy-1-(3-{3-[(propylcarbamoyl)amino]benzene-1-sulfonamido}phenyl)ethyl]carbamoyl}amino)anilino]-1-oxo-5,8,11-
trioxa-2-azatetradecan-14-oyl}-L-α-aspartyl-L-prolyl-L-valinate
antineoplastic, L3KV5NR5PG
Orenasitecan is a small molecule drug. The usage of the INN stem ‘-tecan’ in the name indicates that Orenasitecan is a antineoplastic, topoisomerase I inhibitor. Orenasitecan has a monoisotopic molecular weight of 1470.58 Da.
ORENASITECAN is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
PAT
Cytostatic conjugates with integrin ligands
Publication Number: US-2021386864-A1
Priority Date: 2018-11-05
https://patents.google.com/patent/US20210386864A1
Separation of enantiomers can also be accomplished on different steps via chromatography using chiral columns
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/////////orenasitecan, antineoplastic, L3KV5NR5PG
New Drug Approvals 
